Initial Treatment of Low-grade Non-Hodgkin’s Lymphomas

Bortezomib plus R-CHOP

Bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma. Several studies have suggested that bortezomib has significant activity in patients with aggressive or low-grade NHL. AT ASCO 2009, researchers from Emory University reported Phase I results showing that bortezomib can be added to R-CHOP for the initial treatment of low-grade lymphoma if the dose of vincristine is capped at 1.5 mg. Phase II studies are planned.

Lenalidomide

Lenalidomide is an orally administered derivative of thalidomide that has anti-angiogeneic properties as well as numerous immune and biologic properties. Lenalidomide is approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma and myelodysplastic syndromes. Clinical trials suggest that lenalidomide is active in all subtypes of NHL.

Researchers from the MD Anderson Cancer Center reported that the combination of rituximab and lenalidomide has activity for the initial treatment of patients with previously untreated indolent lymphomas. This early study included 14 evaluable patients for toxicity and five evaluable for response. This combination was well tolerated and four of five patients achieved a CR. Further results will establish the role of this new drug combination for treatment of newly diagnosed patients with indolent lymphoma.

Effects of Maintenance Rituximab

Several randomized Phase III trials have shown that patients with relapsed follicular lymphoma who achieve a remission with rituximab plus chemotherapy benefit from prolonged rituximab maintenance compared with placebo. Rituximab maintenance has also been deemed cost-effective when compared with no maintenance. However, most of these studies have been carried out in patients who have relapsed after initial therapy. Recently, researchers affiliated with the Eastern Cooperative Oncology Group reported that maintenance rituximab given after standard chemotherapy significantly prolongs progression-free survival (PFS) in patients with advanced-stage indolent NHL. Maintenance rituximab therapy began four weeks after completion of the last cycle of CVP and was delivered once per week for four weeks every six months for four courses.

Researchers from Switzerland randomly allocated 270 responding patients with follicular lymphoma to receive rituximab every two months for four doses, or every two months for a maximum of five years. The median duration of prolonged maintenance was 24 months. There is no evidence to date of increased toxicity from prolonged maintenance therapy.

BiovaxID® In Patients with First Complete Remission of Follicular Lymphoma 

BiovaxID is a patient-specific anti-idiotype vaccine that was evaluated in a Phase II trial first reported in 1999. The tumor-specific idiotype is conjugated to keyhole limpet hemocyanin (KLH) and administered with GM-CSF (sargramostim). In this earlier report, eight of 11 patients with detectable translocations on completion of chemotherapy achieved complete remission as determined by the absence of the translocation by polymerase chain reaction (PCR) sequencing following vaccine therapy. All these patients had detectable tumor-specific CD4+ and CD8+ T cells, whereas antibody responses were less frequent and not apparently necessary for clinical remission. At the 2005 meeting of the American Society of Hematology, researchers from the National Cancer Institute and Accentia Pharmaceuticals, Inc. reported nine-year follow-up results of a Phase II study in patients with follicular lymphoma who received BiovaxID after achieving a complete clinical remission; these data led to the current Phase III study. 
At ASCO 2009, researchers involved in a multicenter U.S. clinical Phase III trial have reported that the patient-specific vaccine, BiovaxID, prolongs first remission duration in patients with follicular lymphoma. This Phase III clinical trial included 234 patients with follicular lymphoma who were initially treated with chemotherapy. After remission induction 177 patients who achieved a complete remission (CR) were randomly allocated to receive either BiovaxID or GM-CSF. One-hundred-seventeen patients who had a six-month or greater first remission constituted the study group. There were 76 patients in the BiovaxID group and 41 control patients. At a median follow-up of 56.6 months, the median time to relapse was 44 months in the BiovaxID group and 30.6 months in the control group. These authors concluded: “Id vaccination after a chemotherapy-induced remission of 6 months prolongs remission duration in patients with follicular lymphoma. Compared with other Phase III Id vaccine trials, the positive outcome of this study may reflect application of Id vaccine in patients in CR/Cru or use of hybridomas to produce Id.” These are impressive results and may indicate that BiovaxID will be one of the first vaccines approved by the U.S. Food and Drug Administration.

Treatment of Relapsed Low-grade Lymphomas

Veltuzumab:

Veltuzumab is a humanized monoclonal antibody having 90-95% human antibody sequences that bind to CD20. There are chemical differences between rituximab and veltuzumab which give veltuzumab a longer binding to lymphoma cells. A Phase I-II study of low-dose veltuzumab treatment of adult immune thrombocytopenic purpura was presented at ASH 2008. The study presented at ASCO 2009 involved 19 patients with previously untreated or relapsed indolent NHL or CLL. The preliminary results suggest that veltuzumab has significant activity in low-grade NHL and CLL but it is much to early too conclude that responses are better than observed with rituximab.

Lenalidomide

Clinical trials have also documented activity for lenalidomide in CLL , relapsed or refractory aggressive NHL including mantle cell lymphoma . At ASCO 2009, researchers from the US and Canada presented the results of a Phase II study of lenalidomide in 43 patients with refractory indolent NHL. Patients in this study had received a median of 3 prior regimens. The ORR was 23% with 7% having a CR. The median time to response was 3.6 months. Responses were seen in both follicular lymphoma and small lymphocytic lymphoma. Some responses were durable and the median duration had not been reached at 16.5 months. These authors concluded that “Oral lenalidomide monotherapy produces durable responses with manageable side effects in relapsed or refractory indolent NHL”.

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